Substituted barbituric acid deriva



Patented Jan. 30, 1945 "UNITED/ESTATES PATENT OFFICE SUBSTITUTED BARBITURIC ACID DERIVA- TIVES AND SALTS THEREOF, AND PROC- ESS F PRODUCING THE SAME.

Lewis A. Walter and Louis H. Goodson, East Orange, -N. J assignors to The Maltbie Chemical Company, Newark, N. J., a corporation of New Jersey No Drawing. Application May 14, 1942, Serial No. 443,020

' 28 Claims.

fl'rt present invention relates to certain new and useful 5,5 disubstituted barbituric acid derivatives, and their salts, having useful hypnotic-or sedative properties, and having the formula: g

R-r-S-+'\ /C:NH

'and R has a carbon atom attached directly to the carbon atom of the barbituric acid nucleus; and wherein X is a member of a group consisting of hydrogen, alkali-metal, an equivalent of alkaline-earth metal, ammonium, mono-alkyl ammonium, dialkylammonium, alkanol ammonium and an'equivalent of alkylene diammonium.

These novel compounds, and their salts, which form the subject-matter of the present invention, when tested pharmacologically, have been found to possess useful hypnotic or sedative properties, makingthem valuable for various medical purposes. vThey are, in general, white crystalline solids. t

Our novel barbituric acid derivaties may be prepared by condensing the corresponding disubstituted malonic ester (such as may be prepared, for example, in accordance with United States Letters Patent No. 2,354,234, patented July 25,1944) with urea by means or sodium ethylate, in an organic solvent such as absolute alcohol, and in a manner illustrated by the following equation:

7 (wherein R' is-a lower alkyl group);

Salts of' the compounds may be be prepared as hereafter described.

The following specific examples are illustrative of the novel compounds according to our invention, and of suitable methods for their preparation:

In the following specific illustrative examples the term malonic ester refers, unless otherwise indicated, to the diethyl ester of malonic acid:

EXAMPLE 1 5-n-butyZthi0ethylidene-5-ethyl barbituric acid- CH: O CHaCHaCHzCHr-S( p-NH Seventy-six grams n-butylthloethylidene ethyl malonic ester and 18 grams urea are added to a solution of 12.6 grams of sodium in about 250 cc. absolute alcohol. After refluxing for fourteen hours, the alcohol is removed in a vacuum and the residue dissolved in water and extracted with ether. The aqueous layer is acidified with acetic acid 'and the precipitated 5-n-butylthioethylidene-5-ethyl barbituric acid is filtered off and crystallized from alcohol. It melts at approximately 138-1395 C.

EXAMPLE 2 5-n-butylthioethylidene-5-aZZ2/l barbituric acid CH: ontomontom-scl r OC-NH Following the same procedure as in Example 1, grams of n-butylthioethylidene allyl 'maionic ester is condensed in absolute alcohol with 1'? grams of urea and 14 gram of sodium in the form of sodium ethylate. The desired barbituric acid compound is purified by crystallization from alcohol and melts at approximately 118-119.5 C.

' This compound is prepared from ethylthioisobutylideneethyl malonic esterand urea in the same mannerx-asgiven in Example l, and when recrystallized from alcohol, it melts at 144.5- 145.5 c. I e

, ExAMPLnfl 5-allylthioethylidene-5- isobutylkbarbiturickacid H- I CH3 cH,=c-cHs-o earns H H ,0 i=

This compound is prepared from allylthioethyh "5 idene isobutyl malonic ester and urea in' the same manner asgiyen-in Example and when recrystallized from alcohol, it melts at :155-l{57 C.

.In :the preparation of the novel barbituric acid derivatives according to our invention, the substituent :groups, R,; R and :R", as described ,and defined above, may be varied considerabl within thoselimits, .whilei-producing good results and .useizul and waluable compounds; and among 'the derivatives specifically included in the invention are the following illustrative examples of *our novel derivatives, all ofwhich we have prepared ,and tested v.pharmacologically: j

Baibituric acid In the foregoing, examples 'the melting points are approximate and uncorrected; but are those which we actually observed, according to a. procedurebelievedto be reliable.

While we have not prepared all compounds "falling within the class defined-and claimed-herein, those described-and namedare believed to be -fairlyillustrative of the class. -It is to'be noted, however, that the compounds which we describe andclaim herein are only'comp'ounds "(and their salts) which haveus'eful hypnotic or sedative properties. The present inventionis limited to such compounds, and-we do not claim herein the 9m .l 5= q h q rlisi n fiet y barbituric acid, which is not includ'e'dfin the foregoing list, but which has the formula given under Barbituric acid atthe-head of the list, wherein R is isopropyLRfQis ethylmandeR, is ethyl, and

the melting point iskflpproximately 170-172 C.

That compoundis difierent from all those claimed herein, in that it-has the peculiar and, so far as we know, unique property, among compounds of this general class. of causing spasms or convulsions, often-resulting in violent ,death, if administe'r'ed:intravenously,seven:in, small doses. Neither it, nor any other compound having similar characteristics or properties, is within our present vinvention or the claims hereof.

"mole ofthe'-'appropriate disubstituted barbituric acid in the minimum quantity of hot absolute alcohorand:adding a solution containing one equivalent of sodium in absolute alcohol.

On cooling, or on evaporation of the alcohol, the'sodium salt separates as crystals, or in amorphous form. jIn someinstances, 1a syrup results and this material; when stirred, with dry ether; gives the sodiumysalt in :powder form. I 7

' Q Other 'ailkali-metalsalts may *alsobe Prepared by similar procedure using the appropriate metal.

The sodium salts of our novel barbituric acid derivatives according'to our invention have been .found to be readily soluble in water, and their aqueous solutionsare alkaline in reaction. When administered orallyor hypodermically they are good and useful" hypnotics or sedatives, and range in duration; of action from: long: to u1trashort-acting. v a 1 Calcium salts of ournovel compounds-maybe prepared by treating :an absolute alcohol solution of theicorresponding sodium salt with; the metathetical amount of alcoholic :calcium 'ChIOI'iGB, filtering off the precipitated-sodium chloride and concentrating thewalcoholic solution to ;yield calcium salt. a r

The ammonium, lalkyl and alkanol ammonium salts of our novel compounds may be prepared by dissolving the corresponding barbituric acid in an-excess of ammonia or amineand subsequently remo i the ,excess quantity of, base.

-In=the following claims it is tcbe understood ,thatthe xpression: barbituric acid-derivatives, -or similar expression, includes, -,also, the saltstof v.suc'zh derivatives, ;suchtas,- ior example, i the Salts of our ovel-compo n s zas described-above.

The; examples given: above, and illustrative iprocesseslforz :their production. :include. thefibest embqdimentsmf jour-Presentmvention inowiknown torus; but it ito zbeiunderstoodithat the invenation ,is 1 not ,necessarily or specifically limited thereto andzmay, ,under:propemconditionamave other embodiments, produced in other wayspwlth- ;.out ,departure from -ithe .spiritlxof the :invention,

wherein R andB' are hydrocarbon groups, either saturated or unsaturated, and either the same or "different; R"; is a'saturated hydrocarbon group;

R, R, and'iR '"reach-contain not more than six carbon atoms; and wherein the sum of the carbon atomsin fi, Rf and vR fcioes, not-exceed ten;

R has a carbon atom attached directly to the sulfur of the thiocarbinyl group and R has a carbon atom attached directly to the carbon atom of the barbituric acid nucleus; and wherein X i a member of a group consisting of hydrogen, alkali-metal, an equivalent of alkaline-earth metal, ammoinum, mono-alkyl ammonium, dialkylammonium, alkanol ammonium and an equivalent of alkylene diammonium, and wherein ethyl is excluded as R" when R is isopropyland R is ethyl.

A barbituric compound according to. claim 1 in which X represents hydrogen.

3. A barbituric compound according to claim 1 wherein R, R and R are primary hydrocarbon groups. r

4. A barbituric compound according to claim 1 wherein R, R and R are primary hydrocarbon groups and X represents hydrogen.

5. A barbituric compound according to claim 1 wherein R and R are primary saturated hydrocarbon groups.

6. A barbituric compound according to claim 1 wherein R and R are primary saturated hydrocarbon groups and X represents hydrogen.

7. A barbituric compound according to claim 1 wherein R, R and R" are primary saturated hydrocarbon groups.

8. A barbituric compound according to claim 1 wherein R, R and R" are primary saturated hydrocarbon groups and X represents hydrogen.

9. A barbituric compound according to claim 1 wherein R and R are primary saturated hydrocarbon groups and R" is a methyl group.

10. A barbituric compound according to claim 1 wherein R and R are primary saturated hydrocarbon groups, R is a methyl group and X represents hydrogen.

11. A barbituric compound according to claim 1 wherein R is a, primary saturated hydrocarbon group, R is an ethyl group and R" is a methyl group.

12. A barbituric compound according to claim 1 wherein R is a primary saturated hydrocarbon group, R is an ethyl group, R" is a methyl group and X represents hydrogen.

' 13. A barbituric compound according to claim 1 wherein R is a primary saturated hydrocarbon group containing 5 carbon atoms, R is an ethyl group and R is a methyl group.

14. A barbituric compound according to claim 1 wherein R is a primary saturated hydrocarbon group containing 5 carbon atoms, R is an ethyl group, R" is a methyl group and X represents hydrogen.

17. A barbituric compound according to claim 1 wherein R and R are primary saturated hydrocarbon groups and R" is a secondary hydrocarwherein R and R are primary saturated hydro- Y carbon groups and R is an isopropyl group.

20. A barbituric compound according to claim 1 wherein R and R are primary saturated hydrocarbon groups, R -is an isopropyl group and X represents hydrogen.

21. A barbituric compound according to claim 1 wherein R is a secondary hydrocarbon group; R v

and R are primary hydrocarbon groups.

22. A barbituric compound according to claim 1 wherein R is a secondary hydrocarbon group, R and 'R" are primary hydrocarbon groups and X represents hydrogen.

23. A barbituric compound according to claim 1 wherein R is a secondary hydrocarbon group, R is a primary hydrocarbon group and R is a methyl group.

24. A barbituric compound according to claim 1 wherein R is a secondary hydrocarbon group, R is a primary hydrocarbon group, R" is a methyl group and. X represents hydrogen.

25. A new composition of matter useful in therapeutics, comprising 5-isopropylthioethylidene-S-n-propyl barbituric acid having the formula:

OHsCHzCHa therapeutics, comprising 5-n-amylthioethylidene-5-ethyl barbituric acid having the formula CO-NH CHsCHzCHzCHzCHzS-H\Q/ 0 C245: (JO-I l]?! LEWIS A. WALTER. LOUIS H. GOODSON. 

